Genetic Therapy
Genetic therapy is a recent and highly promising addition to the repertoire of treatments for acquired and inherited diseases. It is expected that many congenital genetic abnormalities and acquired diseases will be amenable to treatment by genetic therapy. Genetic therapy can be effected by removing target cells from an afflicted individual, modifying the cells by introducing heterologous DNA that encodes a therapeutically effective product and returning the modified cells to the individual. Eventually it may be possible to introduce the heterologous DNA directly into cells in vivo (e.g., endothelial cells that line the lungs) without any in vitro manipulation of the target cells.
Diseases that are candidates for such treatment include those that are caused by a missing or defective gene that normally encodes an enzyme, hormone, or other protein. Examples of such diseases include: a severe combined immunodeficiency disorder, which is caused by a defect in the DNA that encodes adenosine deaminase (ADA) (see, e.g., Kredich et al., in The Metabolic Basis of Inherited Disease (5th ed.), Stanbury et al., eds., McGraw-Hill, New York (1983), p. 1157); Lesch Nyhan disease, which is caused by a defect in the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT); cystic fibrosis and Duchenne muscular dystrophy for which the respective defective genes have recently been identified; Tay sachs disease; and hemoglobin disorders, such as .beta.-thalassemia. In addition, genetic therapy has been proposed as a means to deliver therapeutic products, such as tumor necrosis factor (TNF) for the treatment cancers and CD4 receptor protein for the treatment of AIDS (see, e.g., PCT International Application No. WO 90/01870).
Genetic therapy involves introducing heterologous DNA into at least some cells of a host organism in a manner such that the products encoded by the heterologous DNA are expressed in the host. Upon introduction into the host cell, the heterologous DNA may be integrated into the genome of the host cells or it may be maintained and replicated as part of an episomal element. The heterologous DNA may encode products that replace or supplement the product of a defective or absent gene or a gene that is normally expressed at low levels or the DNA may encode therapeutic products that are effective for treating a disease. The heterologous DNA is operatively linked to a promoter and/or other transcriptional and translational regulatory elements that are recognized by host cell effect or molecules, such as RNA polymerase II, such that it can be expressed in the host cell. As understanding of the underlying genetic bases for disease increases, it will be possible to refine the methods of genetic therapy so that regulatory controls that operate at the level of gene transcription or translation or that rely on mechanisms, such as feedback inhibition, to control expression of gene products can also be provided to the host cells. For example, the heterologous DNA may also mediate or encode RNA or protein products that mediate expression of a host cell gene or biochemical process. Expression of the heterologous DNA can thereby be fine-tuned to the needs of the afflicted host.
It is also anticipated that numerous means for introducing heterologous DNA into the cells and genomes of individuals will be developed and refined. At the present time, the use of recombinant viral vectors, which are derived from viruses that infect eukaryotic cells, provide the most promising means for effecting genetic therapy. Generally, upon infection of a eukaryotic host, a virus commandeers the transcriptional and translational machinery of the host cell. In order to do so, vital regulatory signals, such as promoters, particularly those recognized early in infection, tend to be highly efficient so that any DNA that is in operative linkage with such promoters and regulatory signals is efficiently expressed at high levels. Eukaryotic viruses have, therefore, been used as vectors for cloning and expression of heterologous DNA in eukaryotic cells.